PROJECT SUMMARY/ABSTRACT Systemic inflammation is associated with a higher risk of cancer recurrence and mortality among colon cancer patients. Systemic inflammation promotes the growth and progression of existing micro-metastases and the development of new distant metastases. Reducing systemic inflammation may decrease the risk of developing recurrent and metastatic disease among colon cancer patients. Epidemiologic data suggests that physical activity after diagnosis of colon cancer reduces the risk of recurrence and mortality by 50%. Physical activity possesses potent anti-inflammatory properties. However, the extent to which physical activity can normalize the host microenvironment by interrupting the crosstalk between inflammation and the growth and progression of existing micro-metastases and the development of new distant metastases is not known. We hypothesize that physical activity mediates the relationship between inflammation and cancer recurrence and mortality. Aim 1 will determine if physical activity mediates the relationship between plasma inflammatory markers and cancer recurrence and mortality among colon cancer patients. To complete this aim, we will utilize data from a recently-completed NCI-sponsored trial among 2,526 colon cancer patients. Aim 2 will determine preliminary effect size estimates for two distinct doses of exercise to reduce plasma inflammatory markers among colon cancer patients. To complete this aim, we will utilize data from a recently-completed NCI-sponsored phase II trial that randomized 39 colon cancer patients to low-dose (150 min/wk) or high-dose (300 min/wk) moderate- intensity aerobic exercise or a usual care control group for six-months. The results from Aims 1 and 2 will guide the design and implementation of Aim 3, which will determine the efficacy of exercise to reduce plasma inflammatory markers among colon cancer patients. To complete this aim, we will conduct an adequately- powered prospective randomized trial among colon cancer patients. This research and training plan will: 1) provide the advanced transdisciplinary training necessary to accelerate the translation of epidemiologic discoveries into efficacious individual and population level interventions; 2) position the applicant to emerge as an international leader in the field of energy balance and cancer outcomes research, and; 3) validate a translational platform on which to examine other biologic pathways to be funded through future research project grant programs (R01s). Understanding how physical activity may alter inflammation to favorably influence disease outcomes among colon cancer patients offers unique insight into colon cancer biology and provides new paradigms in cancer therapy by optimizing treatment strategies and identifying additional therapeutic targets. This research aligns with an NCI key priority area to elucidate the molecular basis through which exercise may influence cancer outcomes, towards the goal of optimizing exercise prescription to maximize patient outcomes.